Triazole fused heteroaryl compounds and methods of use thereof

ABSTRACT

The present invention comprises a new class of compounds useful for modulating the activity of p38 MAP kinase. The compounds have a general Formula I 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , R 1  and R 5  are defined herein. The invention further provides pharmaceutical compositions including one or more compounds of Formula I, use of such compounds and compositions for treatment of p38 MAP kinase mediated diseases including rheumatoid arthritis, psoriasis and other inflammatory disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/994,806, filed 21 Sep. 2007, which specification is herebyincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treat variousdisorders, including TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseasesand other maladies, such as inflammation and pain. The invention alsorelates to intermediates and processes useful in the preparation of suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation is atransfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. Protein tyrosine kinases (PTKs) are enzymes, which catalyze thephosphorylation of specific tyrosine residues in cellular proteins.Examples of kinases in the protein kinase family include, withoutlimitation, ab 1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellularprocesses, protein kinases have emerged as important therapeutictargets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating inflammatorycytokine production via various pathways. Uncontrolled or excessivecytokine production has been observed in many disease states, andparticularly in those related to inflammation.

The p38 protein kinase has been reported to be involved in theregulation of inflammatory cytokines. Interleukin-1 (IL-1) and TumorNecrosis Factor α (also referred to herein as TNF-α or TNF) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide (LPS)) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis (RA); osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease (IBD); adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; boneresorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

TNF-α has been reported to play a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14:615 (1994)). In a rat model of ischemia wherein themiddle cerebral artery was occluded, the levels of TNF-α mRNA of TNF-αincreased (Feurstein et al., Neurosci. Lett., 164:125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke 25:1481 (1994)).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated therewith. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)).Landevirta et al., (Am. J. Med. 85:289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8. Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type IIdiabetes; bone resorption diseases; ischemia reperfusion injury;atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock;and toxic shock syndrome. Viruses sensitive to TNF-α inhibition, e.g.,HIV-1, HIV-2, HIV-3, are also affected by IL-1.

Antagonism of TNF-α has been reported to be beneficial for treatinguveitis (Reiff et al, A&R 44:141-145 (2001)); Sepsis (Abraham, Lancet,351:929 (1998)); Systemic Lupus Erythrematosis (SLE) (Aringer, A&R,50:3161 (2004)); Graft vs Host Disease (Couriel, Curr. Opinion Oncology,12:582 (2000)); Polymyositis and Dermatomyositis (Labiache,Rheumatology, 43:531 (2004)); Type II diabetes (Ruan, Cytokine GFReview, 14:447 (2003)); Sjogren's disease (Marriette, A&R, 50:1270(2004)), Sarcoidosis (Roberts, Chest, 124:2028 (2003)); Wegener'sgranulomatosis (WGET, New England J. Med., 352:351 (2005)) and post MIcardiac dysfunction (Sugano et al, Mol. Cell. Bioch., 266:127 (2004)).In addition, TNF-α has been reported to play a role in SAPHO, periodicfever, relapsing polychrondritis, multicentric reticulohistiocytosis,macrophage activation syndrome, Hyper IgD syndrome, familial Hibernianfever, Pyoderma gangrenosum, Cochleovestibular disorders, Cicatricalpemphigoid, Herniated intervertebral disc diseases, amyloidosis, CINCAsyndrome, myelodisplastic syndrome, alcoholic hepatitis, andendometriosis. Finally, indications which have already been approved fortreatment with a therapeutic agent which modulates TNF-α levels in theplasma, and/or other pro-inflammatory cytokines, include withoutlimitation, inflammatory bowel disease (IBD), psoriatis arthritis,ankylosing spondylitis and juvenile RA.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus, glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction. Elevation of glucose levels along with the reducedexpression of IL-1Ra, an antagonist of IL-1 signaling, leads to impairedinsulin secretion, decreased cell proliferation and apoptosis Inhibitonof IL-1 action has been shown to improve glycemia, b-cell secretoryfunction and reduce markers of systemic inflammation (Larsen, NewEngland J. Med., 356: 1517 (2007).

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 led to an acute and destructive form of arthritis(Chandrasekhar et al., Clinical Immunol Immunopathol., 55:382 (1990)).In studies using cultured rheumatoid synovial cells, IL-1 is a morepotent inducer of stromelysin than is TNF-α (Firestein, Am. J. Pathol.,140:1309 (1992)). At sites of local injection, neutrophil, lymphocyte,and monocyte emigration has been observed. The emigration is attributedto the induction of chemokines (e.g., IL-8), and the up-regulation ofadhesion molecules (Dinarello, Eur. Cytokine Netw., 5:517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol., 136:40 (1986)). Beutler et al. (J. Immunol., 135:3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J.Med., 308:553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis (RA), both IL-1 and TNF-α induce synoviocytesand chondrocytes to produce collagenase and neutral proteases, whichleads to tissue destruction within the arthritic joints. In an in-vivoanimal model of arthritis, i.e., collagen-induced arthritis (CIA) inrats and mice, intra-articular administration of TNF-α either prior toor after the induction of CIA led to an accelerated onset of arthritisand a more severe course of the disease (Brahn et al., LymphokineCytokine Res. 11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244(1992)). IL-1 and TNF-a have been implicated in pro-inflammatorymechanisms in many human diseases including inflammatory arthritis,inflammatory bowel disease sepsis syndrome and both acute and cheonisinflammation of many organs. (Vassali P., The Pathophysiology of TumorNecrosis Factors, Ann. Rev. Immunology 10: 411-452 (1992) and DinarelloC A, Biologic Basis for Interluekin-1 in disease, Blood, 87:2095-2147(1996)).

IL-6 also appears to play a role in, and therefore have applications to,pro-inflammatory and other malignant diseases. Particularly, deregulatedlevels of IL-6 are associated with various immunological diseases, suchas RA, systemic juvenile idiopathic arthritis (sJIA), polyarticular typeJIA, systemic lupus erythematosus (SLE), vasculitis syndrome, CastlemanDisease and Crohn's Disease; transplantation conditions such as acuterejection and graft-versus-host disease (GVHD); respiratory diseasessuch as interstitial pneumonia and bronchial; asthma; bone diseases suchas osteoporosis and Paget's disease, as well as various malignantdisease including multiple myeloma, renal cancer, prostate cancer,cardiac mixoma, Kaposis sarcoma, Mesothelioma, Malignant lymphoma, lungcancer and gastric cancer. (Nishimoto and Kishimoto, Review, 2: 619-625(2006)). It follows that the reduction and/or regulation of IL-6 levelsmay be useful for treatment of one or more of the above diseases.

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

The role and activity of the p38 protein in RA and otherpro-inflammatory cytokine mediated diseases and conditions are becomingbetter understood. For example, Korb et al., Arthritis and Rheumatism,54: 2745-2756 (2006) describes the activation of the p38 alpha (p38α)and p38 gamma (p38γ) and the role which these two isoforms play in thedevelopment and progression of RA. Korb further describes thecorrelation between expression of p38 and the incidence of CRP in RA.Korb has found that the expression of these isoforms dominate inpatients with chronic inflammation and, therefore, concludes thateffective strategies to inhibit p38 kinase should aim to specificallytarget either or both of the isoforms. Medicherla et al., J.Pharmacology and Experimental Therapeutics, 318, 132-141 (2006) andNishikawa et al., Arthritis & Rheumatism, 48, 2670-2681 (2003) describeresults of an in-vivo collegan-induced arthritis (CIA) model in the ratand mouse. More specifically, they report that, in both animals,inhibition of p38α activity and related signaling improved clinicalscore and reversed bone and cartilage destruction. Ferrari,Cardiovascular Research 37:554 (1998) and Jacobsson et al., J Rheum.32:1213 (2005) describe how pro-inflammatory cytokines, such as TNF andIL-1, play a role in cadiovascular disease. More specifically, they havefound that blocking or reducing the levels of TNF-α have a protectiveeffect, and reduce the incidence of cardiovascular disease in RApatients. Behr et al., Circulation, 104, 1292 (2001) describes theability and efficacy of a p38 kinase inhibitor in treating hypertensivecardiac hypertrophy.

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.195-223 (1995)). These approaches block the effects of TNF-α and IL-1 byeither protein sequestration or receptor antagonism.

Yet another approach to block the effect of TNF-α, and otherpro-inflammatory cytokines, has been to modulate the activity of the p38kinase enzyme. For example, the PCT publication, WO 04/010995, publishedon Feb. 5, 2004, describes fused heteroaryl derivatives for use as p38kinase inhibitors in the treatment of I.A. and rheumatoid arthritis; PCTpublication, WO 2005/009937, published on Feb. 3, 2005, describes5-membered heterocycle-based p38 kinase inhibitors; U.S. Pat. No.6,635,644, issued Oct. 21, 2003, describes fused nitrogen-containingbicyclic ring systems as p38 inhibitors; and U.S. Pat. No. 6,794,380,issued Sep. 21, 2004, describes amide derivatives as p38 inhibitors.Despite the ongoing efforts, there needs to be effectiveanti-inflammatory agents which regulate the production ofpro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and/or IL-8.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful in theprophylaxis and treatment of pro-inflammatory cytokine mediateddisorders and disease. In particular, the compounds of the invention areuseful for the prophylaxis and treatment of TNF-α, IL-1β, IL-6 and/orIL-8 mediated diseases and other maladies, such as pain and diabetes. Inaddition, the invention provides pharmaceutical compositions comprisingthe compounds described herein, methods for the prophylaxis andtreatment of TNF-α, IL-1β, IL-6 and/or IL-8 mediated diseases, such asinflammatory, pain and diabetes diseases, using the compounds andcompositions of the invention, and intermediates and synthetic processesuseful for the preparation of the compounds of the invention.

The compounds provided by the invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, are defined by general Formula I

wherein A¹, A², A³, A⁴, A⁵, A⁶, R¹ and R⁵ are as defined below. Theinvention also provides procedures for making compounds of Formula I,compounds of Formula II, and intermediates useful in such procedures.

The compounds provided by the invention are capable of modulating thep38 kinase enzyme. To that end, the compounds of the invention may beused for therapeutic, prophylactic, acute and/or chronic treatment ofp38 kinase mediated diseases, such as those described herein. Forexample, the compounds are useful for the prophylaxis and treatment ofdiseases or conditions involving inflammation.

The invention further provides pharmaceutical compositions, alsocommonly referred to as “medicaments”, comprising one or more of thecompounds of the invention in combination with one or morepharmaceutically acceptable carrier(s) or excipient(s). Suchcompositions may be useful to attenuate, alleviate, or treat p38kinase-mediated disorders through inhibition of the activity of the p38kinase enzyme.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention provides compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, which are generally defined by FormulaI:

wherein

A¹ is CR² or N;

A² is CR³ or N;

each of A³, A⁴, A⁵ and A⁶, independently, is CR⁴ or N, provided that nomore than two of A³, A⁴, A⁵ and A⁶, independently, is N;

R¹ is —(CR⁷R⁷)_(n)X or —(CR⁷R⁸)_(n)X, wherein n is 0, 1 or 2 and X isC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂R⁷,S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸,

or X is a 3-8 membered monocyclic or 6-12 membered bicyclic ring system,said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁷, R⁸ or R⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN, OR⁹,SR⁹, NR⁹R⁹, C(O)R⁹, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R⁸ or R⁹;

each R⁴, independently, is H, halo, haloalkyl, NO₂, CN, —OR⁹, —SR⁹,—NR⁹R⁹ or —C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁹;

R⁵ is NR¹⁰R¹⁰, NR¹⁰R¹¹, OR¹⁰, SR¹⁰, OR¹¹, SR¹¹, C(O)R¹⁰, C(NCN)R¹⁰,C(O)R¹¹, C(NCN)R¹¹, C(O)C(O)R¹⁰, OC(O)R¹⁰, COOR¹⁰, C(O)C(O)R¹¹,OC(O)R¹¹, COOR¹¹, C(O)NR¹⁰R¹⁰, C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹⁰, NR¹⁰C(O)NR¹⁰R¹¹, NR¹⁰(O)OR¹⁰,NR¹⁰C(O)OR¹¹, NR¹⁰C(O)C(O)R¹⁰, NR¹⁰C(O)C(O)R¹¹, NR¹⁰C(O)C(O)NR¹⁰R¹¹,S(O)₂R¹⁰, S(O)₂R¹¹, S(O)₂NR¹⁰R¹⁰, S(O)₂NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹,NR¹⁰S(O)₂R¹⁰ or NR¹⁰S(O)₂R¹¹;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸,OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸,NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹),OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹,NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated3-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, NO₂, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₂₋₁₀-alkynyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with oneor more substituents of R¹¹, R¹² or R¹⁶, NR¹¹R¹², NR¹²R¹², OR¹¹, SR¹¹,OR¹², SR¹², C(O)R¹¹, OC(O)R¹¹, COOR¹¹, C(O)R¹², OC(O)R¹², COOR¹²,C(O)NR¹¹R¹², NR¹²C(O)R¹¹, C(O)NR¹²R¹², NR¹²C(O)R¹², NR¹²C(O)NR¹¹R¹²,NR¹²C(O)NR¹²R¹², NR¹²(COOR¹¹), NR¹²(COOR¹²), OC(O)NR¹¹R¹², OC(O)NR¹²R¹²,S(O)₂R¹¹, S(O)₂R¹², S(O)₂NR¹¹R¹², S(O)₂NR¹²R¹², NR¹²S(O)₂NR¹¹R¹²,NR¹²S(O)₂NR¹²R¹², NR¹²S(O)₂R¹¹, NR¹²S(O)₂R¹², NR¹²S(O)₂R¹¹ orNR¹²S(O)₂R¹²;

R¹¹ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁶;

alternatively, R¹⁰ and R¹¹ taken together form a partially or fullysaturated or unsaturated 5-6 membered ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, and the ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁶;

R¹² is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R¹⁵ or R¹⁶;

R¹⁵ is H or C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl or C₁₋₁₀-thioalkoxyl, each of which is optionallysubstituted independently with 1-5 substituents of R¹⁶; and

R¹⁶ is H, H halo, haloalkyl, CN, OH, NO₂, NH₂, OH, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, butyl, isobutyl,tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino,isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or apartially or fully saturated or unsaturated 3-8 membered monocyclic or6-12 membered bicyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl,methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino,benzyl or phenyl.

In one embodiment, the invention provides compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, which are generally defined by FormulaI:

wherein

A¹ is CR² or N;

A² is CR³ or N;

A³ is CR⁴;

each of A⁴, A⁵ and A⁶, independently, is CR⁶ or N, provided that no morethan two of A³, A⁴, A⁵ and A⁶, independently, is N;

R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈-alkyl,—N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₃₋₈-cycloalkyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl, NO₂, CN,C₁₋₆-alkyl, C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹;

R⁴ is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl, —OC₁₋₆-alkyl,—SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl of each isoptionally comprising 1-3 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁹;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁶, independently, is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹;

each R⁷, independently, is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl andC₃₋-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR^(S), C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl,

provided that R¹ is not —C(Phenyl)₃.

In another embodiment, the compounds of Formula I include compoundswherein A³ is CR⁴ and each of A⁴, A⁵ and A⁶, independently, is CR⁶, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A³ and A⁴, independently, is CR⁴ and CR⁶, respectively,and each of A⁵ and A⁶, independently, is CH, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of A³ and A⁴, independently, is H, halo, haloalkyl,haloalkoxyl or C₁₋₄alkyl, and each of A⁵ and A⁶, independently, is CH,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein two of A⁴, A⁵ and A⁶, independently, is CR⁶ and the other one ofA⁴, A⁵ and A⁶, independently, is N, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein two of A³, A⁴, A⁵ and A⁶, independently, is CR⁴ and the othertwo of A³, A⁴, A⁵ and A⁶, independently, is N, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A³ is CR⁴ and R⁴ is H, halo, haloalkyl, NO₂, NH₂, CN, OH,OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl, NHC₁₋₄-alkyl, C(O)C₁₋₄-alkylor C₁₋₄-alkyl optionally substituted with one or more substituents ofR⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A³ is CR⁴ and R⁴ is H, halo, haloalkyl, OC₁₋₄-alkyl,OC₁₋₄-haloalkyl or C₁₋₄-alkyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A³ is CR⁴ and R⁴ is H, F, Cl, Br, methyl, methoxyl, ethyl,ethoxyl, CF₃ or CHF₂, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A⁴ is CR⁶ and R⁶ is H, halo, haloalkyl, NO₂, NH₂, CN, OH,OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl, NHC₁₋₄-alkyl, C(O)C₁₋₄-alkylor C₁₋₄-alkyl optionally substituted with one or more substituents ofR⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A⁵ is CR⁶ and R⁶ is H, halo, haloalkyl, NO₂, NH₂, CN, OH,OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl, NHC₁₋₄-alkyl, C(O)C₁₋₄-alkylor C₁₋₄-alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A⁶ is CR⁶ and R⁶ is H, halo, haloalkyl, NO₂, NH₂, CN, OH,OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl, NHC₁₋₄-alkyl, C(O)C₁₋₄-alkylor C₁₋₄-alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of R⁴ and each R⁶, independently, is H, halo, haloalkyl,NO₂, CN, —OR⁹, —SR⁹, —NR⁹R⁹ or —C₁₋₁₀-alkyl optionally substituted withone or more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each of R⁴ and each R⁶, independently, is H, halo, haloalkyl,NO₂, NH₂, CN, OH, OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl,NHC₁₋₄-alkyl, C(O)C₁₋₄-alkyl or C₁₋₄-alkyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the invention provides compounds, andstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, which are generally defined by FormulaII

wherein

A¹ is CR² or N;

A² is CR³ or N;

each of A⁴, A⁵ and A⁶, independently, is CR⁶ or N, provided that no morethan one of A³, A⁴, A⁵ and A⁶, independently, is N;

R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclorhexyl, each of C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ring optionallysubstituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃, methyl or ethyl;

R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH,

—O-methyl, —S-methyl, —NH-methyl, —N(methyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁷;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH,—O-methyl, —S-methyl, —NH-methyl, —N(methyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁷;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-3 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein said ring is optionally substitutedindependently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₄₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl,

provided that R¹ is not —C(Phenyl)₃.

In another embodiment, the compounds of Formula II include compoundswherein each of CR and each CR⁶, independently, is H, halo, haloalkyl,NO₂, NH₂, CN, OH, OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl,NHC₁₋₄-alkyl, C(O)C₁₋₄-alkyl or C₁₋₄-alkyl optionally substituted withone or more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II include compoundswherein each of R⁴ and each R⁶, independently, is H, halo, haloalkyl,NO₂, NH₂, CN, OH, OC₁₋₄-alkyl, OC₁₋₄-haloalkyl, SC₁₋₄-alkyl,NHC₁₋₄-alkyl, C(O)C₁₋₄-alkyl or C₁₋₄-alkyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula II include compoundswherein R⁴ is H, halo, haloalkyl, NO₂, NH₂, CN, OH, OC₁₋₃-alkyl,OC₁₋₃-haloalkyl, SC₁₋₃-alkyl, NHC₁₋₃-alkyl, C(O)C₁₋₃-alkyl or C₁₋₃-alkyloptionally substituted with 1-5 substituents of halo;

A⁴ is R⁶ wherein R⁶ is H, halo, haloalkyl, NO₂, NH₂, CN, OH,OC₁₋₄-alkyl, SC₁₋₄-alkyl, NHC₁₋₄-alkyl, C(O)C₁₋₄-alkyl or C₁₋₄-alkyloptionally substituted with one or more substituents of R⁹;

A⁵ is R⁶ wherein R⁶ is H, halo, haloalkyl or C₁₋₄-alkyl optionallysubstituted with one or more substituents of R⁹; and

A⁶ is R⁶ wherein R⁶ is H, halo, haloalkyl or C₁₋₄-alkyl optionallysubstituted with one or more substituents of R⁹, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I or Formula II includecompounds wherein A¹ is N and A² is CR³, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I or Formula II includecompounds wherein each of A¹ is CR² and A² is N, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I or Formula II includecompounds wherein each of A¹ is CR² and A² is CR³, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I or Formula II includecompounds wherein each of A¹ and A² is CH, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I or Formula II includecompounds wherein each of A¹ and A² is N, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formulas I or II includecompounds wherein R² is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I or II includecompounds wherein compounds wherein each of A¹ is CR² and R² is H, halo,haloalkyl or C₁₋₁₀-alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I or II includecompounds wherein compounds wherein each of A² is CR³ and R³ is H, halo,haloalkyl or C₁₋₁₀-alkyl, in conjunction with any of the above or belowembodiments.

In one embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl,—NHC₁₋₈-alkyl, —N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of which is optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl,—NHC₁₋₆-alkyl, —N alkyl)₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₆-cycloalkyl, each of which is optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, neo-pentyl, isopentyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, —OC₁₋₄-alkyl, —SC₁₋₄-alkyl,—NHC₁₋₄-alkyl or —N(C₁₋₄-alkyl)₂, each of which is optionallysubstituted with 1-5 substituents of R⁹, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I and Formula IIincludes compounds wherein R¹ is methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, pentyl, neopenyl, hexyl, cyclopropyl,cyclopentyl, cyclohexyl or allyl, each of which is optionally comprising1-4 heteroatoms selected from N, O and S and optionally substituted withone or more substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, morpholinyl, piperidinyl,piperazinyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,morpholinyl, piperidinyl, piperazinyl, each of which is optionallysubstituted independently with 1-5 substituents of R⁹, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a phenyl, pyridyl, pyrimidyl, pyridazinyl orpyrazinyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is a phenyl optionally substituted independentlywith 1-5 substituents of R⁹, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, neo-pentyl, isopentyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, —OC₁₋₄-alkyl, —SC₁₋₄-alkyl,—NHC₁₋₄-alkyl or —N(C₁₋₄-alkyl)₂, each of which is optionallysubstituted with 1-5 substituents of R⁹, or R¹ is a ring selected fromphenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, each ring of whichis optionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl or C₁₋₆-aminoalkyl, each of which are optionallysubstituted with 1-5 substituents of R⁹, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, halo, haloalkyl or C₁₋₆-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, halo, methyl or ethyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, F, Cl, methyl or ethyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R² is H, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl or C₁₋₆-aminoalkyl, each of which are optionallysubstituted with 1-5 substituents of R⁹, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, halo, haloalkyl or C₁₋₆-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, halo, methyl or ethyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, F, Cl, methyl or ethyl, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R³ is H, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each of R² and R³, independently, is H or halo, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each of R² and R³, independently, is H, F, Cl, methylor ethyl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each of R² and R³, independently, is H or F, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each of R² and R³, independently, is H, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁴ is fluoro, chloro, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl orneopentyl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁴ is Fluoro, chloro, methyl, ethyl, propyl, butyl,isobutyl or pentyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁴ is methyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each R⁶, independently, is H, halo, haloalkyl, NO₂,CN, OH, C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, whereinthe C₁₋₆-alkyl of each is optionally comprising 1-3 heteroatoms selectedfrom N, O and S and optionally substituted with 1-5 substituents of R⁹,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃,C₂F₅, —OC₂F₅, —OC₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —SC₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₆-alkyl optionally substituted with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃,C₂F₅, —OC₂F₅, —OCH₃, —SCH₃, —NHCH₃, NO₂, NH₂, OH, CN, methyl, ethyl orpropyl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each R⁶, independently, is H, F, Cl, Br, CF₃, —OCH₃,—NHCH₃, OH, CN, methyl or ethyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein each R⁶, independently, is H, F, Cl, Br, OH, CN ormethyl, in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction withany of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸,in conjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁵ is C(O)NHC₁₋₆-alkyl, C(O)NHC₂₋₆-alkenyl,C(O)NHC₂₋₆-alkynyl, C(O)NHC₃₋₆-cycloalkyl, C(O)NHaryl, C(O)NHheteroaryl,NHC(O)C₁₋₆-alkyl, NHC(O)C₂₋₆-alkenyl, NHC(O)C₂₋₆-alkynyl,NHC(O)C₃₋₆-cycloalkyl, NHC(O)aryl or NHC(O)heteroaryl, in conjunctionwith any of the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁵ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸, in conjunction with anyof the above or below embodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclorhexyl, each of which isoptionally substituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, halo, haloalkyl or C₁₋₄-alkyl;

R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁷;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with one or moresubstituents of R⁷;

each R⁷, independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, whereinthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula I andFormula II wherein R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl,—NHC₁₋₆-alkyl or a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, morpholinyl, piperidinyl,piperazinyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclorhexyl, eachof C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ringoptionally substituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃, methyl or ethyl;

R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl, —S-methyl,—NH-methyl, —N(methyl)₂, NO₂, NH₂, CN or C₁₋₆-alkyl, the C₁₋₆-alkyloptionally substituted with one or more substituents of R⁹;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸;

each R⁶, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH,—O-methyl, —S-methyl, —NH-methyl, —N(methyl)₂, NO₂, NH₂, CN orC₁₋₆-alkyl, the C₁₋₆-alkyl optionally substituted with one or moresubstituents of R⁹;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-3 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein said ring is optionally substitutedindependently with 1-3 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₂₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formulas I or II includecompounds wherein each R⁹, independently, is H, F, Cl, Br, CF₃, —OCF₃,C₂F₅, —O—C₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, OH,C₁₋₁₀ alkyl or a ring selected from phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of F, Cl,Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂,NO₂, NH₂, CN, OH or C₁₋₁₀-alkyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the invention provides compounds, andstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, which are generally defined by FormulaIII

wherein

A¹ is CR² or N;

A² is CR³ or N;

R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclorhexyl, each of C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ring optionallysubstituted with 1-5 substituents of R⁹;

each of R² and R³, independently, is H, F, Cl, CF₃, methyl or ethyl;

R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl, —S-methyl,—NH-methyl, —N(methyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁷;

R⁶ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl, —S-methyl,—NH-methyl, —N(methyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with one or more substituents of R⁷;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-3 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, wherein said ring is optionally substitutedindependently with 1-3 substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-alkylamino-,C₁₋₁₀-cycloalkenyl, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl,

provided that R¹ is not —C(Phenyl)₃.

In yet another embodiment, the compounds of Formulas I, II and IIIinclude each of the examples, and pharmaceutically acceptable salts andstereoisomers thereof, described hereinbelow.

In yet another embodiment, the invention provides a compound, or apharmaceutically acceptable salt form thereof, selected from

-   -   4-methyl-N-(1-methylethyl)-3-(1-(1-methylethyl)-1H-1,2,3-benzotriazol-5-yl)benzamide;    -   N-cyclopropyl-4-methyl-3-(1-(1-methylethyl)-1H-benzotriazol-5-yl)benzamide;    -   3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;    -   3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-N-cyclopropyl-4-methylbenzamide;    -   N-cyclopropyl-3-fluoro-5-(1-(4-fluoro-2-methylphenyl)-1H-benzotriazol-5-yl)-4-methylbenzamide;    -   3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-5-fluoro-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;    -   N-cyclopropyl-3-(1-(1,1-dimethylethyl)-1H-benzotriazol-5-yl)-5-fluoro-4-methylbenzamide;        and    -   N-cyclopropyl-3-fluoro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-benzotriazol-5-yl)benzamide.

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). Examplesof such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tent-butyl, pentyl, isoamyl, hexyl and the like.The term “alkylenyl” embraces bridging divalent alkyl radicals such asmethylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Examples of alkenylradicals include, without limitation, ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of such radicals include,without limitation, ethynyl, propynyl (propargyl), butynyl, and thelike.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means an aromaticcarbocyclic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. Unless otherwise specified, the “aryl”group may be substituted, such as with 1 to 5 substituents includinglower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and loweralkylamino, and the like. Phenyl substituted with —O—CH₂—O— or—O—CH₂—CH₂—O— forms an aryl benzodioxolyl substituent.

The term “cycloalkyl”, also referred to herein as “carbocyclic”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane andpartially saturated monocyclic groups such as cyclopentene, cyclohexeneor cyclohexadiene. The partially saturated groups are also encompassedin the term “cycloalkenyl” as defined below.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of heteroaryl radicals, include unsaturated 5- to 6-memberedheteromonocyclyl groups containing 1 to 4 nitrogen atoms, including forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces bicyclic radicals wherein 5- or6-membered heteroaryl radicals are fused/condensed with aryl radicals orunsaturated condensed carbocyclic or heterocyclic groups containing 1 to5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturatedcondensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated,partially unsaturated and unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one more heteroatomsselected from N, O or S. Examples of heterocyclic radicals includesaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “Formula I” includes any sub formulas, such as Formula II andIII. Similarly, the term “Formula II” and “Formula III” includes any subformulas.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I, II or III is intended to refer to a form orcomponent of the compound that has been acceptable by a regulatoryagency for administration to a subject. For example, a free base, a saltform, a solvate, a hydrate, a prodrug or derivative form of a compoundof Formula I or of Formula II, which has been approved for mammalianuse, via oral ingestion or any other route of administration, by agoverning body or regulatory agency, such as the Food and DrugAdministration (FDA) of the United States, is pharmaceuticallyacceptable.

Included in the compounds of Formulas I and II are the pharmaceuticallyacceptable salt forms of the free-base compounds. Suitable salt forms,include those alkali metal salts, generally used to form addition saltsof free acids or free bases, which have been approved by a regulatoryagency. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I and II may be prepared from an inorganic acid or from anorganic acid. Examples of such inorganic acids are hydrochloric (HCl),hydrobromic (HBr), hydroiodic (HI), hydrofluoric (HF), nitric (HNO3),carbonic, sulfonic, sulfuric and phosphoric acid.

Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, pamoic, pectinic, persulfuric,2-phenylpropionic, picric, pivalic propionic, succinic, thiocyanic,undecanoic, stearic, algenic, β-hydroxybutyric, salicylic, galactaricand galacturonic acid. Suitable pharmaceutically-acceptable baseaddition salts of compounds of Formulas I and II include metallic salts,such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I, II or III.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative, which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formula I. A “pharmaceutically-acceptable prodrug” as usedherein, denotes a prodrug, which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of Formula I,II or III are readily appreciated by those of ordinary skill in the art.

The compound(s) of Formula I, II or III may be used to treat a subjectby administering the compound(s) as a pharmaceutical composition. Tothis end, the compound(s) can be combined with one or more excipients,including carriers, diluents or adjuvants, to form a suitablecomposition, which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.

The terms “treat”, “treating” and “treatment” as used herein refer totherapy, including without limitation, curative therapy, prophylactictherapy, and preventative therapy. Prophylactic treatment generallyconstitutes either preventing the onset of disorders altogether ordelaying the onset of a pre-clinically evident stage of disorders inindividuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “leaving groups” (also denoted as “LG”) generally refer togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I, II and III. The compounds of Formulas I, IIand III can be synthesized according to the procedures described in thefollowing Schemes 1-6, wherein the substituents are as defined forFormulas I, II and III, above, except where further noted. The syntheticmethods described below are merely exemplary, and the compounds of theinvention may also be synthesized by alternate routes as appreciated bypersons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresents the following and should assist in understanding theinvention:

ACN, MeCN—acetonitrileBSA—bovine serum albuminBOP—benzotriazol-1-yl-oxy hexafluorophosphateCDI—carbonyldiimidazoleCs₂CO₃—cesium carbonateCHCl₃—chloroformCH₂Cl₂, DCM—dichloromethane, methylene chlorideDCC—dicyclohexylcarbodiimideDIC—1,3-diisopropylcarbodiimideDIEA,(iPr)₂NEt—diisopropylethylamineDME—dimethoxyethaneDMF—dimethylformamideDMAP—4-dimethylaminopyridineDMSO—dimethylsulfoxideEDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimideEt₂O—diethyl etherEtOAc—ethyl acetateG, gm—gramh, hr—hourH₂—hydrogenH₂O—waterHATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHBr—hydrobromic acidHCl—hydrochloric acidHOBt—1-hydroxybenzotriazole hydrateHOAc—acetic acidHPLC—high pressure liquid chromatographyIPA, IpOH—isopropyl alcoholK₂CO₃—potassium carbonateLG—leaving groupMgSO₄-magnesium sulfateMS—mass spectrumMeOH—methanolN₂—nitrogenNaCNB H₃—sodium cyanoborohydrideNa₂CO₃—sodium carbonateNaHCO₃—sodium bicarbonateNaH—sodium hydrideNaOCH₃—sodium methoxideNaOH—sodium hydroxideNa₂SO₄—sodium sulfate

NBS—N-bromosuccinimide

NH₄Cl—ammonium chlorideNH₄OH—ammonium hydroxide

NMP—N-methylpyrrolidinone

P(t-bu)₃—tri(tert-butyl)phosphinePBS—phospate buffered salinePd/C—palladium on carbonPd(PPh₃)₄—palladium(0)triphenylphosphine tetrakisPd(dppf)Cl₂—palladium(1,1-bisdiphenylphosphinoferrocene) II chloridePd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloridePd(OAc)₂—palladium acetatePd₂(dba)₃—tris(dibenzylideneacetone) dipalladiumPyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphoniumhexafluorophosphateRT—room temperatureTBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborateTEA, Et₃N—triethylamineTFA—trifluoroacetic acidTHF—tetrahydrofuranUV—ultraviolet light

Benzotriazoles 6, (where each of A¹ and A² in Formula I is CH or CR² andCR³, respectively, and wherein R⁵ is an amide linker as shown,connecting R⁷ and R⁸ to the central ring (generally referred to as the“B” ring; the “B” ring may generally be an optionally substitutedphenyl, pyridinyl or pyrimidyl ring) may be made by the method generallydescribed in Scheme 1, also designated herein as Method A. As shown, abis-amino substituted bromobenzene 3 may be made from fluoro-nitro-bromobenzene 1 as described. The fluorine of starting material 1 may bedisplaced with a suitable nucloephilic species, such as the amine asshown above, to afford the corresponding amino-substituted compound 2.The nitro group of compound 2 can then be reduced using conventionalmethods, including iron/acetic acid as shown, to the amino form,compound 3.

The triazole ring of compound 4 may be made from compound 3 by closingthe ring, using suitable reagents and methods. For example, compound 3may be reacted with NaNO₂ in the presence of a suitable acid, such asHCl and HOAc, to afford the ring-closed benzotriazole adduct 4. Thebromide of compound 4 can then used to build the bond between thebenzotrizole ring and the “B” ring, using known, conventional reactionmethods, such as the Suzuki reaction. As shown, a desired R⁵-substituted“B” ring intermediate 5 (here R⁵ is shown as an amide linked R⁷ andR^(7 or 8)) may be used under suitable Suzuki Coupling conditions, suchas those shown in scheme 1, with a desired bromo-benzotriazoleintermediate 4 to afford the desired substituted compounds 6 of FormulasI, II or III. The boronic ester intermediates 5 may be prepared bymethods described in PCT Patent Appl. No. WO2005073189 and PCT PatentAppl. No. WO2006094187.

The Suzuki method is a reaction using a borane reagent, such as adioxaborolane intermediate 5, and a suitable leaving group containingreagent, such as the Br-benzotriazole 4 (Br is a suitable halogenleaving group “LG”). As appreciated to one of ordinary skill in the art,Suzuki reactions also utilize a palladium catalyst. Suitable palladiumcatalysts include Pd(PPh₃)₄, Pd(OAc)₂ or Pd(dppf)Cl₂. Where LG is ahalide, the halide may be an iodide, a bromide or even a chloride(chloro-pyridyl or chloro-picolinyl B rings undergo Suzuki reactions inthe presence of Pd(OAc)₂). Other LGs are also suitable. For example,Suzuki couplings are known to occur with a sulfonate, such astrifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such astoluene, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Further, the reaction may require heatdepending upon the particular benzotriazole 4 and/or boronic acid orester 5, as appreciated by those skilled in the art. In addition, wherethe B ring is an aromatic moiety, such as phenyl, the reaction may becomplete in a short period of time with heat.

Other methods of installing the boronate on a desired aromatic ring areknown. For example metal coupling chemistry, such Stille, Kumada,Negishi coupling methods, and the like, may be employed to couple adesired benzotriazole core 4 to a desired B-ring-substitutedintermediate.

Various other linker R⁵ groups are within the scope of the presentinvention. Such other linkers may be made using the general methodsdescribed in scheme 2 below. As illustrate in scheme 2, desirable R⁷ andR⁸ groups are shown as a ring designated as ring A. However, the presentinvention is not so limited, and it is intended that what is depicted as“ring A” in scheme 2 should be read to also include non cyclic moietiesattached to linker R⁵, as described in Formulas I, II and III herein.

The B ring, as illustrated in scheme 2, is substituted by a linker groupR⁵. The R⁵ linker group, including an amino, a carboxyl, a sulfonyl, anamido or a urea linker, as defined herein in Formulas I and II, connectvarious substitutions, including R⁷ non-cyclic moieties or R⁷ and R⁸cyclic rings (generally designated and referred to in Scheme 2, andthroughout the specification, as the “A” group or “A” ring) to the “B”ring. This linker may be attached by various coupling methods asdescribed in Scheme 2. Each of the nine sub-schemes, numbered 1-9 aboveand described below, utilize the following meanings for (R)_(n), X, Nu⁻,E⁺ and m: (R)_(n) refers to n number of R⁷, R⁸ and R⁹ substitutionswherein n is an integer from 0-5; X refers generally to a “leavinggroup” (also referred to herein as “LG”) such as a halide (bromine,chlorine, iodine or fluorine), alkylsulfonate and other known groups(also see definitions herein); Nu⁻ refers generally to a nucleophilicspecies such as a primary or secondary amine, an oxygen, a sulfur or aanionic carbon species—examples of nucleophiles include, withoutlimitation, amines, hydroxides, alkoxides and the like; E⁺ refersgenerally to an electrophilic species, such as the carbon atom of acarbonyl, which is susceptible to nucleophilic attack or readilyeliminates—examples of suitable electrophilic carbonyl species include,without limitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated with activatingreagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP and carbodiimides(DCC, EDC, CDI and the like), and other electrophilic species includinghalides, isocyanates, daizonium ions and the like; and m is either 0 or1.

The coupling of ring B to A, as shown as products in sub-schemes 1-9,can be brought about using various conventional methods to link ring Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 7 and 9 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A groupsand an acid chloride or sulfonyl chloride on the other of either the Bor A groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, anhydrous solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof. The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-schemes 5 and 1 where Nu− isan amine, anhydrides as illustrated in sub-scheme 1 where Nu− is anoxygen, reverse amides as generally illustrated in sub-scheme 8 whereNu− is an amine and E+ is an acid chloride, ureas as illustrated insub-scheme 3, thioamides and thioureas where the respective carbonyloxygen is a sulfur, thiocarbamates where the respective carbonyl oxygenand/or carbamate oxygen is a sulfur, and the like. While the abovemethods are so described, they are not exhaustive, and other methods forlinking groups A and B together may be utilized as appreciated by thoseskilled in the art.

Although sub-schemes 1-9 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A group or B ring, in question, the invention is not solimited. It is contemplated herein that these nucleophilic and/orelectrophilic coupling groups may be tethered from their respectivering. For example, the amine group on the B ring, and/or the acid halidegroup on the A group or ring, as illustrated in sub-scheme 2, may beremoved from direct attachment to the ring by a one or more atom spacer,such as by a methylene, ethylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to effect the desired transformation.

The coupling methods described in sub-schemes 1-9 of scheme 2 are alsoapplicable for coupling desired A groups or rings to desiredpyrazolo-pyridinone-B ring intermediates, such as to substituted B ringcarboxylic acids (Example 2) to synthesize desired compounds of FormulasI and II. For example, a desirably substitutedpyrazolo-pyridinone-benzoic acid maybe reacted with a desirablysubstituted primary or secondary amine, such as an NHR⁷R⁷ or NHR⁷R⁸group in the presence of a suitable solvent and a known couplingreagent, such as TBTU, HATU, CDI or others, to prepare the desired A-Bamide bond, and the final compound of Formulas I, II or III.

Note that the B-A moiety is connected through a linker “L”. “L” may beany linker generally defined by the R⁵ groups in Formulas I and II, andparticularly, it includes, without limitation, an amide, a urea, athiourea, a thioamide, a carbamate, an anhydride, a sulfonamide and thelike, allowing for spacer atoms either between ring B and L and/orbetween ring or group A and L, as described in Scheme 6 above.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I, II and III) and methods of making compounds ofthe invention are set forth. It should be appreciated that the abovegeneral methods and specific examples below are merely for illustrativepurposes only and are not to be construed as limiting the scope of thisinvention in any manner. The following analytical methods were used topurify and/or characterize the compounds, and intermediates, describedin the examples below.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with an AgilentTechnologies XDB-C₈ (3.5μ) reverse phase column (4.6×75 mm) at 30° C.The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% HOAc) and solventB (ACN/0.1% HOAc) with a 9 min time period for a gradient from 10% to90% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods: (A) Using a 50×100 mm column (Waters, Exterra, C18,5 microns) at 50 mL/min. The mobile phase used was a mixture of solventA (H₂O/10 mM ammonium carbonate at pH about 10, adjusted with conc.NH₄OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH ofabout 10 adjusted with conc. NH₄OH). Each purification run utilized a 10minute gradient from 40% to 100% solvent B followed by a 5 minute flowof 100% solvent B. The gradient was followed by a 2 min return to 40%solvent B. (B) Using a 20×50 mm column at 20 mL/min. The mobile phaseused was a mixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1%TFA) with a 10 min gradient from 5% to 100% solvent B. The gradient isfollowed by a 2 min return to 5% ACN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

Example 1 Via Method A

Preparation of3-(1-(2-Chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamideStep 1: N-(4-Bromo-2-nitrophenyl)-2-chlorobenzenamine

A mixture of 1-bromo-4-fluoro-3-nitrobenzene (3.00 mL, 13.6 mmol),2-chloroaniline (2.87 mL, 27.3 mmol) and potassium fluoride (0.792 g,13.6 mmol) was heated at 180° C. for 48 h. Upon cooling the mixture, DCM(300 mL) was added and the mixture was successively washed with water(100 mL), 10% HCl (2×50 mL) and brine (50 mL). The resulting organicsolution was dried over magnesium sulfate and concentrated under reducedpressure. The resulting crude material was purified by flashchromatography on SiO₂(DCM:hexanes=25:75) to afford the title compoundas a red crystalline solid. MS (ESI, pos. ion) m/z: 328.9 (M+1).

Step 2: 4-Bromo-N-1-(2-chlorophenyl)benzene-1,2-diamine

To a 250-mL round-bottomed flask equipped with a stir bar and refluxcondenser was added N-(4-bromo-2-nitrophenyl)-2-chlorobenzenamine (2.00g, 6.11 mmol), glacial acetic acid (2.47 ml, 42.7 mmol) and EtOH (60mL). The mixture was heated to 60° C. at which point the suspensionbecame a clear orange solution. Iron powder (325 mesh, 1.02 g, 18.3mmol) was added in one portion and the mixture was heated to reflux.Heating was continued for 3 h. The hot reaction mixture was filteredthrough a pad of Celite, rinsed with hot MeOH (2×50 ml). The filtratewas concentrated down to about 10 ml, treated with 30 mL of 2 N HCl,extracted with 3×100 mL of EtOAc. The combined EtOAc layer was washedsequentially with brine (50 mL) followed by sat. sodium thiosulfate (50mL), brine (50 mL), then dried and concentrated to afford the titlecompound as a dark solid. This crude material was used in the next stepwithout further purification. MS (ESI, pos. ion) m/z: 298.9 (M+1).

Step 3: 5-Bromo-1-(2-chlorophenyl)-1H-benzo[d1][1,2,3]triazole

To a solution of 4-bromo-N-1-(2-chlorophenyl)benzene-1,2-diamine (1.66g, 5.58 mmol) in glacial acetic acid (10 mL) and 5 N HCl (10 mL) wasadded sodium nitrite (577 mg, 8.37 mmol) in 10 mL of water at 0° C.slowly. The reaction mixture was stirred at RT for 3 h, then poured onto 50 g of ice and neutralized by adding 2 N NaOH drop wise. Theresulting mixture was extracted with EtOAc (3×60 mL). The combinedorganic solution was washed with brine, dried over magnesium sulfate andconcentrated under reduced pressure. Purification was effected by flashchromatography on SiO₂ (10-35% of EtOAc in Hexanes) to afford the titlecompound as a dark crystalline solid. MS (ESI, pos. ion) m/z: 309.9(M+1).

Step 4:3-(1-(2-Chlorophenyl)-1H-benzo[d][1,2,3]triazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide

To a mixture ofN-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(100 mg, 0.31 mmol),5-bromo-1-(2-chlorophenyl)-1H-benzo[d][1,2,3]triazole (110 mg, 0.34mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) indioxane (3 mL) was added 1.3 mL of 2 N sodium carbonate solution. Thereaction mixture was heated at 125° C. in a microwave for 30 min. Themixture was then treated with 2 mL of 1 N NaOH and extracted with 2×15mL of EtOAc. The combined organic phase was washed with brine, driedover magnesium sulfate and concentrated under reduced pressure. Theresulting crude material was purified by flash chromatography on silicalgel (30-70% of EtOAc in Hexanes) to give the title compound as an offwhite crystalline solid. MS (ESI, pos. ion) m/z: 421.0 (M+1).

Example 2 Preparation of 4-Bromo-N-tert-butyl-2-nitrobenzenamine

To a solution of t-butylamine (1.3 mL, 13 mmol) in DMSO (15 mL) wasadded sodium hydride (60% wt. in mineral oil, 0.53 g, 14 mmol) at RT.After the reaction mixture was stirred for 10 min, it was treated with1-bromo-4-fluoro-3-nitrobenzene (2.0 mL, 9.1 mmol). The reaction mixturewas stirred at RT for 1 h the 70° C. for 3 h. After cooling to RT, itwas quenched with 50 mL of water and extracted with DCM (3×40 mL). Thecombined organic phases were washed with 2 N HCl followed by brine. Theresulting organic solution was then dried over magnesium sulfate andconcentrated under reduced pressure to give4-bromo-N-tert-butyl-2-nitrobenzenamine as a red crystalline solid. Thecrude product was used without further purification. MS (ESI, pos. ion)m/z: 273.9 (M+1).

Example 3 Preparation of 4-Bromo-N-isopropyl-2-nitrobenzenamine

To a stirred, cold (0° C.) solution of 4-bromo-1-fluoro-2-nitrobenzene(7 g, 32 mmol) in dichloromethane (100 mL) was added isopropylamine (5mL, 64 mmol). The mixture was allowed to stir at 0° C. for 3 h and roomtemperature overnight. It was diluted with water and extracted withCH₂Cl₂. The organic layer was washed with water and brine, dried(MgSO₄), and filtered. The filtrate was concentrated in vacuo to give acrude red solid. Trituration with MeOH afforded the title compound as anorange-red solid. MS (ESI, pos. ion) m/z: 260.7 (M+1).

The following Examples in Table 1 will further assist in understandingand appreciating the invention. However, in no way is the following listof compounds intended to limit the scope of the invention. The compoundsof examples 4-10 were made in accordance with exemplary method A whichcorresponds to Example 1 above, and named according to the ACD namingconvention, as associated with ISIS software. The mass spectral data isrecorded M+H+, which is the positive ion as measured by an electrosprayionization method.

TABLE 1 LPS THP-1 induced cell IL-1 cell based assay assay p38a Ex. MSIC₅₀ IC₅₀ IC₅₀ No Name (M + H+) (uM) (uM) (uM) 44-methyl-N-(1-methylethyl)-3-(1-(1- 337.2 + ++ +++++methylethyl)-1H-1,2,3-benzotriazol- 5-yl)benzamide 5N-cyclopropyl-4-methyl-3-(1-(1- 335.2 + ++++ +++++methylethyl)-1H-benzotriazol-5- yl)benzamide 6 3-(1-(2-chlorophenyl)-1H-421.0 +++ +++++ +++++ benzotriazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide 7 3-(1-(2-chlorophenyl)-1H- 403.2 + ++++ +++++benzotriazol-5-yl)-N-cyclopropyl-4- methylbenzamide 8N-cyclopropyl-3-fluoro-5-(1-(4- 419.1 +++ +++++ +++++fluoro-2-methylphenyl)-1H- benzotriazol-5-yl)-4- methylbenzamide 93-(1-(2-chlorophenyl)-1H- 461.1 ++++ +++++ +++++benzotriazol-5-yl)-5-fluoro-4-methyl- N-(1-methyl-1H-pyrazol-5-yl)benzamide 10 N-cyclopropyl-3-(1-(1,1- 367.2 + +++++ +++++dimethylethyl)-1H-benzotriazol-5-yl)- 5-fluoro-4-methylbenzamide 11N-cyclopropyl-3-fluoro-4-methyl-5- 395.2 ++++ ++++(1-(tetrahydro-2H-pyran-4-yl)-1H- benzotriazol-5-yl)benzamide Data Key:“+” designates an IC₅₀ value in the range beginning from 1.0 uM andending at 5.0 uM; “++” designates an IC₅₀ value in the range beginningfrom 250 nM and ending at 1.0 uM; “+++” designates an IC₅₀ value in therange beginning from 100 nM and ending at 250 nM; “++++” designates anIC₅₀ value in the range beginning from 25 nM and ending at 100 nM; and“+++++” designates an IC₅₀ value of less than 25 nM.

The following compounds in Tables 2 and 3 are additional representativeexamples of Formula I, as provided by the present invention.

TABLE 2

Ex. No. R¹ R⁶ R⁵ R⁷ or R⁸ 12 3,5-difluoro-Ph H —C(O)NH— oxazolyl 13morpholine H —C(O)NH— methyl or cyclopropyl 14 piperazine H —C(O)NH—methyl or cyclopropyl 15 piperidine H —C(O)NH— ethyl or cyclopropyl 16phenyl F —C(O)NH— propyl or cyclopropyl 17 m-CH₃-phenyl- Cl —C(O)NH—methyl or cyclopropyl 18 m-Cl-phenyl- OCH₃ —C(O)NH— methyl orcyclopropyl 19 3,5-difluoro-Ph H —C(O)NH— isoxazolyl 20 morpholine H—C(O)NH— pyrazolyl 21 piperazine H —C(O)NH— imidazolyl 22 piperidine H—C(O)NH— triazolyl 23 phenyl F —C(O)NH— tetrazolyl 24 m-CH3-phenyl- Cl—C(O)NH— thioazolyl 25 2-cl-phenyl OCH3 —C(O)NH— isothiazolyl 262-CH3-phenyl H —NHC(O)— phenyl 27 4-CH3-phenyl H —NHC(O)— cyclopropyl 284-cl-phenyl di-F —NHC(O)— ethyl 29 3-cl-phenyl di-Cl —NHC(O)— propyl 303-CH3-phenyl OCH3 —NHC(O)— butyl 31 2-thiophene CF3 —NHC(O)— isopropryl32 3-thiophene OCF3 —NHC(O)— isobutyl 33 2-pyridine OH —NHC(O)—cyclopentyl 34 1-morpholinyl F —C(O)NH— ethyl 35 1-piperazinyl Cl—C(O)NH— ethyl 36 1-piperidinyl OCH3 —C(O)NH— ethyl 37 3,5-difluoro-Ph F—C(O)NH— ethyl 38 3-cl-phenyl Cl —C(O)NH— ethyl 39 3-CH3-phenyl OCH3—C(O)NH— ethyl 40 2-thiophene H —C(O)NH— ethyl 41 phenyl —NHCH3 —NH—isoxazolyl 42 3-amido-1- H —NH— pyrazolyl pyrrolidinyl 433-amido-1-piperidinyl H —NH— imidazolyl 44 4-amido-1-piperidinyl F —NH—triazolyl 45 4N—CH3-1-piperizinyl Cl —C(O)— tetrazolyl 46 2-cl-phenylOCH3 —C(O)— thioazolyl 47 2-CH3-phenyl F —C(O)— isothiazolyl 484-CH3-phenyl Cl —C(O)— phenyl 49 4-cl-phenyl OCH3 —C(O)NH— cyclopropyl50 3-cl-phenyl F —C(O)NH— ethyl 51 3-CH3-phenyl —NHCH3 —C(O)NH— propyl52 2-thiophene H —C(O)NH— ethyl 53 3-thiophene H —C(O)NH— ethyl 542-pyridine F —C(O)NH— ethyl 55 1-morpholinyl Cl —C(O)NH— cyclopropyl 561-piperazinyl CN —NHC(O)— propyl 57 1-piperidinyl CF3 —NHC(O)—cyclopropyl 58 cyclohexyl-N— OH —NHC(O)— cyclopropyl 59morpholine-(CH2)2—N NHCH3 —NHC(O)— propyl 60 (CH3)2N—(CH2)2— H —NHC(O)—propyl 61 (C2H5)2N—(CH2)2— acetyl —NHC(O)— cyclopropyl 623-OH-1-pyrrolidinyl H —NHC(O)— propyl 63 —CH2CH3— H —NHC(O)— propyl 64—(CH2)2CH3— acetyl —C(O)NH— isoxazolyl 65 —CH3— H —C(O)NH— pyrazolyl 664N-CH3-1-piperizinyl H —C(O)NH— imidazolyl 67 2-cl-phenyl H —C(O)NH—triazolyl 68 2-CH₃-phenyl H —C(O)NH— tetrazolyl 69 4-CH₃-phenyl CN—C(O)NH— thioazolyl 70 4-cl-phenyl H —S(O)₂NH— isothiazolyl 713-cl-phenyl H —NH— phenyl 72 3-CH₃-phenyl H —NH— cyclopropyl 732-thiophene H —NH— ethyl 74 3-thiophene H —NH— propyl 75 2-pyridine H—C(O)— isoxazolyl 76 4-F-phenyl CH₃ —C(O)— pyrazolyl

TABLE 3

Ex. No. R¹ R⁶ R⁵ R⁷ or R⁸ 77 3-thiophene H —C(O)NH— Methyl orcyclopropyl 78 2-pyridine F —C(O)NH— Methyl or cyclopropyl 791-morpholinyl Cl —C(O)NH— Methyl or cyclopropyl 80 1-piperazinyl Br—NHC(O)— Methyl or cyclopropyl 81 1-piperidinyl OH —NHC(O)— Methyl orcyclopropyl 82 cyclohexyl-N— CN —NHC(O)— Methyl or cyclopropyl 83morpholine-(CH₂)₂—N— H —NHC(O)— Methyl or cyclopropyl 84 (CH₃)₂N—(CH₂)₂—H —NHC(O)— Methyl or cyclopropyl 85 (C₂H₅)₂N—(CH₂)₂— H —NHC(O)— Methylor cyclopropyl 86 3-OH-1- H —NHC(O)— Methyl or pyrrolidinyl cyclopropyl87 —CH₂CH₃— F —NHC(O)— Methyl or cyclopropyl 88 —(CH₂)₂CH₃— F —C(O)NH—Methyl or cyclopropyl 89 —CH₃— F —C(O)NH— Methyl or cyclopropyl 904N—CH₃-1- F —C(O)NH— Methyl or piperizinyl cyclopropyl 91 2-cl-phenyl F—C(O)NH— Methyl or cyclopropyl 92 2-CH₃-phenyl F —C(O)NH— Methyl orcyclopropyl 93 4-CH₃-phenyl H —C(O)NH— Methyl or cyclopropyl 944-cl-phenyl H —S(O)₂NH— Methyl or cyclopropyl 95 3-cl-phenyl H —NH—Methyl or cyclopropyl 96 3—CH₃-phenyl H —NH— Methyl or cyclopropyl 972-thiophene H —NH— Methyl or cyclopropyl 98 3-thiophene F —NH— ethyl 992-pyridine F —C(O)— ethyl 100 4-F-phenyl F —C(O)— ethyl 101 3-thiopheneF —C(O)— ethyl 102 morpholine-(CH₂)₂— F —NH— ethyl 103 (CH₃)₂N—(CH₂)₂— F—NH— ethyl 104 (C₂H₅)₂N—(CH₂)₂— H —NH— cyclopropyl 105 3-OH-1- H —NH—propyl pyrrolidinyl 106 3-amido-1- H —NH— cyclopropyl pyrrolidinyl 1073-amido-1- F —NH— cyclopropyl piperidinyl 108 4-amido-1- F —NH— propylpiperidinyl 109 4N-CH₃-1- F —NH— propyl piperizinyl 110 2-cl-phenyl F—NH— cyclopropyl 111 2-CH₃-phenyl F —NH— propyl 112 4-CH₃-phenyl F —NH—propyl 113 4-cl-phenyl H —NH— isoxazolyl 114 3-cl-phenyl H —NH—pyrazolyl 115 3-CH₃-phenyl H —NH— imidazolyl 116 2-thiophene H —NH—triazolyl 117 3-thiophene F —NH— tetrazolyl 118 2-pyridine F —NH—thioazolyl 119 1-morpholinyl F —NH— isothiazolyl 120 1-piperazinyl F—NH— phenyl 121 1-piperidinyl H —NH— cyclopropyl 122 cyclohexyl- H —NH—ethyl 123 morpholine-(CH₂)₂— H —NH— propyl 124 (CH₃)₂N—(CH₂)₂— H—C(O)NH— isoxazolyl 125 (C₂H₅)₂N—(CH₂)₂— F —C(O)NH— pyrazolyl 1263-OH-1- F —C(O)NH— ethyl pyrrolidinyl 127 3-amido-1- F —C(O)NH— ethylpyrrolidinyl 128 3-amido-1- F —NH— cyclopropyl piperidinyl 1294-amido-1- F —NH— propyl piperidinyl 130 4N—CH₃-1- F —NH— propylpiperizinyl 131 2-cl-phenyl H —NH— propyl 132 2-CH₃-phenyl H —NH—isopropyl 133 4-CH₃-phenyl H —NH— propyl 134 4-cl-phenyl H —NH— propyl135 3-cl-phenyl F —NH— isopropyl 136 3-CH₃-phenyl F —NH— propyl 1372-thiophene F —NH— isopropyl 138 3-thiophene H —NH— allyl 139 2-pyridineH —NH— propyl 140 4-F-phenyl CH₃ —NH— cyclopropyl

While the examples described above provide processes for synthesizingcompounds of Formulas I, II and III, it should be appreciated that othermethods may be utilized to prepare such compounds. Methods involving theuse of protecting groups may be used. Particularly, if one or morefunctional groups, for example carboxy, hydroxy, amino, or mercaptogroups, are or need to be protected in preparing the compounds of theinvention, because they are not intended to take part in a specificreaction or chemical transformation, various known conventionalprotecting groups may be used. For example, protecting groups typicallyutilized in the synthesis of natural and synthetic compounds, includingpeptides, nucleic acids, derivatives thereof and sugars, having multiplereactive centers, chiral centers and other sites potentially susceptibleto the reaction reagents and/or conditions, may be used.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosauren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide and Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., ethyl acetate; ethers includingaliphatic ethers, e.g., Et₂O and ethylene glycol dimethylether or cyclicethers, e.g., THF; liquid aromatic hydrocarbons, including benzene,toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n-and t-butanol; nitriles including CH₃CN; halogenated hydrocarbons,including CH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides,including DMSO; bases, including heterocyclic nitrogen bases, e.g.pyridine; carboxylic acids, including lower alkanecarboxylic acids,e.g., AcOH; inorganic acids including HCl, HBr, HF, H₂SO₄ and the like;carboxylic acid anhydrides, including lower alkane acid anhydrides,e.g., acetic anhydride; cyclic, linear, or branched hydrocarbons,including cyclohexane, hexane, pentane, isopentane and the like, andmixtures of these solvents, such as purely organic solvent combinations,or water-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inselect embodiments, such starting materials are used and reactionconditions so selected as to obtain the desired compound(s).

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

In synthesizing a compound of formulas I, II and III according to adesired procedure, the steps may be performed in an order suitable toprepare the compound, including a procedure described herein or by analternate order of steps described herein, and may be preceded, orfollowed, by additional protection/deprotection steps as necessary. Theprocedures may further use appropriate reaction conditions, includinginert solvents, additional reagents, such as bases (e.g., LDA, DIEA,pyridine, K₂CO₃, and the like), catalysts, and salt forms of the above.The intermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase, and thelike), extraction, distillation, trituration, reverse phase HPLC and thelike. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the inhibitor compounds described herein are known in theart and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd)edition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995). In oneembodiment, the present invention provides a the method comprising thestep of reacting a compound 7

wherein A¹, A² and R¹ are as defined herein and X is a halogen, with aboronic acid having a general formula

wherein A³, A⁴, A⁵ A⁶ and R⁵ as defined herein, to make a compound ofFormulas I, II or III.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers including, without limitation, racemates and racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the present invention.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The compounds of this invention may contain heterocyclic ring systemsattached to another ring system. Such heterocyclic ring systems may beattached through a carbon atom or a heteroatom in the ring system.

The present invention also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this inventioncan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

Biological Evaluation

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion. By way of example, a compound ofthe invention may be modified to incorporate a hydrophobic group or“greasy” moiety in an attempt to enhance the passage of the compoundthrough a hydrophobic membrane, such as a cell wall.

Although the pharmacological properties of the compounds of theinvention (Formulas I, II and III) vary with structural change, ingeneral, activity possessed by compounds of Formulas I, II and III maybe demonstrated both in vitro as well as in vivo. Particularly, thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays. The followingexemplified pharmacological assays have been carried out with thecompounds according to the invention. Compounds of the invention werefound to inhibit the activity of various kinase enzymes, including,without limitation, p38 receptor kinase at doses less than 25 μm.

The following assays were used to characterize the ability of compoundsof the invention to inhibit the production of TNF-α and interleukincytokines, including IL-1, IL-1-β, Il-6 and IL-8. The second assay canbe used to measure the inhibition of TNF-α and/or IL-1-β in mice afteroral administration of the test compounds. The third assay, a glucagonbinding inhibition in vitro assay, can be used to characterize theability of compounds of the invention to inhibit glucagon binding. Thefourth assay, a cyclooxygenase enzyme (COX-1 and COX-2) inhibitionactivity in vitro assay, can be used to characterize the ability ofcompounds of the invention to inhibit COX-1 and/or COX-2.

p38 In-Vitro HTRF Enzyme Assay

The compounds of the invention can be tested for their respectiveaffinities for the p38 protein using a conventional p38 in-vitro enzymeactivity assay. For example, a P38-alpha HTRF assay may be used tomeasure the protein's in-vitro phosphorylation activity, and the dataanalyzed using time resolved fluorimetry techniques (FRET). A p38 HTRFassay is as follows. The kinase reaction buffer for p38α, p38β, p38δ andp38γ HTRF assays consists of 50 mM Tris-pH 7.5, 5 mM MgCl₂, 0.1 mg/mLBSA, 100 μM Na₃VO₄ and 0.5 mM DTT. The HTRF detection buffer contains100 mM HEPES-pH 7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween-20, and 10 mMEDTA. Each compound was dissolved in 100% DMSO and serially diluted (3fold, 10 point) in a polypropylene 96-well microtiter plate (drugplate). The final starting concentration of the compound in the p38α□and p38β enzymatic assays was about 1 μM. The final startingconcentration of each compound in the p38δ and p38γ enzymatic assays wasabout 10 μM. The p38α, p38β, p38δ and p38γ kinase reactions were carriedout in a polypropylene 96-well black round bottom assay plate in totalvolume of 30 μL kinase reaction buffer. Appropriate concentration ofpurified and activated enzyme (recombinant human) was mixed withindicated concentration of ATP and 100 nM GST-ATF2-Avitag, in thepresence or absence (HI control) of each compound. In the absence ofenzyme, the background was measured as LO control. HI controls and LOcontrols contained only DMSO. The reaction was allowed to incubate for 1hour at RT. The kinase reaction was terminated and phospho-ATF2 wasrevealed by addition of 30 μL of HTRF detection buffer supplemented with0.1 nM Eu-anti-pTP and 4 nM SA-APC. After 60 minutes incubation at roomtemperature, the assay plate was read in a Discovery Plate Reader. Thewells were excited with coherent 320 nm light and the ratio of delayed(50 ms post excitation) emissions at 620 nM (native europiumfluorescence) and 665 nm (europium fluorescence transferred toallophycocyanin—an index of substrate phosphorylation) was determined(Park et al, 1999). The resulting data was analyzed by taking theproportion of substrate phosphorylated in the kinase reaction in thepresence of each individual compound and comparing it with thatphosphorylated in the presence of DMSO vehicle alone (HI control). Thedata was calculated using the formula: % control (POC)=(compound−averageLO)/(average HI−average LO)*100. Data (consisting of POC and inhibitorconcentration in μM) was fitted to a 4-parameter equation(y=A+((B−A)/(1+((x/C)̂D))), where A is the minimum y (POC) value, B isthe maximum y (POC), C is the x (compound concentration) at the point ofinflection and D is the slope factor, using a Levenburg-Marquardtnon-linear regression algorithm. The inhibition constant (Ki) of theinhibitor was estimated from the IC₅₀ (compound concentration at thepoint of inflection C) using the Cheng-Prussof equation:Ki=IC₅₀/(1+S/Km), where S is the ATP substrate concentration, and Km isthe Michaelis constant for ATP as determined experimentally. All resultswere expressed as the mean±the standard error of the mean. Dataacquisition and non-linear regression algorithms were performed usingActivity Base v5.2 and XLfit software v4.1 respectively. Additionalassay information may be obtained in Park Y W, Cummings R T, Wu L, etal. Homogeneous Proximity Tyrosine Kinase Assays: ScintillationProximity Assay versus Homogeneous Time-Resolved Fluorescence.Analytical Biochemistry. 1999; 269: 94-104. Biological data (IC₅₀ valueranges) for Examples 1-10 for this assay is provided in Table 1.

Lipopolysaccharide-Activated Monocyte TNF Production Assay Isolation ofMonocytes

Test compounds were evaluated in vitro for the ability to inhibit theproduction of TNF by monocytes activated with bacteriallipopolysaccharide (LPS). Fresh residual source leukocytes (a byproductof plateletpheresis) were obtained from a local blood bank, andperipheral blood mononuclear cells (PBMCs) were isolated by densitygradient centrifugation on Ficol-Paque Plus (Pharmacia). PBMCs weresuspended at 2×10⁶/mL in DMEM supplemented to contain 2% FCS, 10 mM, 0.3mg/mL glutamate, 100 U/mL penicillin G and 100 mg/mL streptomycinsulfate (complete media). Cells were plated into Falcon flat bottom, 96well culture plates (200 μL/well) and cultured overnight at 37° C. and6% CO₂. Non-adherent cells were removed by washing with 200 μl/well offresh medium. Wells containing adherent cells (˜70% monocytes) werereplenished with 100 μL of fresh medium.

Preparation of Test Compound Stock Solutions

Test compounds were dissolved in DMZ. Compound stock solutions wereprepared to an initial concentration of 10-50 μM. Stocks were dilutedinitially to 20-200 μM in complete media. Nine two-fold serial dilutionsof each compound were then prepared in complete medium.

Treatment of Cells with Test Compounds and Activation of TNF Productionwith Lipopolysaccharide

One hundred microliters of each test compound dilution were added tomicrotiter wells containing adherent monocytes and 100 μL completemedium. Monocytes were cultured with test compounds for 60 min at whichtime 25 μL of complete medium containing 30 ng/mL lipopolysaccharidefrom E. coli K532 were added to each well. Cells were cultured anadditional 4 hrs. Culture supernatants were then removed and TNFpresence in the supernatants was quantified using an ELISA.

TNF ELISA

Flat bottom, 96 well Corning High Binding ELISA plates were coatedovernight (4° C.) with 150 μL/well of 3 μg/mL murine anti-human TNF-αMAb (R&D Systems #MAB210). Wells were then blocked for 1 h at roomtemperature with 200 μL/well of CaCl₂-free ELISA buffer supplemented tocontain 20 mg/mL BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mMCaCl₂, 0.15 mM thimerosal, pH 7.4). Plates were washed and replenishedwith 100 μL of test supernatants (diluted 1:3) or standards. Standardsconsisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/mLrecombinant human TNF (R&D Systems). Plates were incubated at roomtemperature for 1 h on orbital shaker (300 rpm), washed and replenishedwith 100 μL/well of 0.5 μg/mL goat anti-human TNF-α (R&D systems#AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40min, washed and replenished with 100 μL/well of alkalinephosphatase-conjugated streptavidin (Jackson ImmunoResearch#016-050-084) at 0.02 μg/mL. Plates were incubated 30 min, washed andreplenished with 200 μL/well of 1 mg/mL of p-nitrophenyl phosphate.After 30 min, plates were read at 405 nm on a V_(max) plate reader.

Data Analysis

Standard curve data were fit to a second order polynomial and unknownTNF-α concentrations determined from their OD by solving this equationfor concentration. TNF concentrations were then plotted vs. testcompound concentration using a second order polynomial. This equationwas then used to calculate the concentration of test compounds causing a50% reduction in TNF production. Exemplary compounds 1-10 exhibitedactivities in the whole blood monocyte assay (LPS induced TNF release)with IC₅₀ values of 2.5 μM or less.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from monocytes by measuringconcentrations of IL-1β, IL-6 and/or IL-8 by methods well known to thoseskilled in the art. In a similar manner to the above described assayinvolving the LPS induced release of TNF-α from monocytes, compounds ofthis invention can also be shown to inhibit LPS induced release ofIL-1β, IL-6 and/or IL-8 from monocytes by measuring concentrations ofIL-1β, IL-6 and/or IL-8 by methods well known to those skilled in theart. Thus, the compounds of the invention may lower elevated levels ofTNF-α, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of theseinflammatory cytokines to basal levels or below is favorable incontrolling, slowing progression, and alleviating many disease states.The data (IC₅₀ value ranges) for Examples 1-10 for this assay isprovided in Table 1.

Lipopolysaccharide-Activated THP1 Cell TNF Production Assay

THP1 cells are resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1XPGS, 1XNEAA, plus 30 μM βME) at a concentrationof 1E6/mL. One hundred microliters of cells per well are plated in apolystyrene 96-well tissue culture. One microgram per mL of bacterialLPS is prepared in THP1 media and is transferred to the wells. Testcompounds are dissolved in 100% DMSO and are serially diluted 3-fold ina polypropylene 96-well microtiter plate (drug plate). HI control and LOcontrol wells contain only DMSO. One microliter of test compound fromthe drug plate followed by 10 μL of LPS are transferred to the cellplate. The treated cells are induced to synthesize and secrete TNF-α at37° C. for 3 h. Forty microliters of conditioned media are transferredto a 96-well polypropylene plate containing 110 μL of ECL buffer (50 mMTris-HCl pH 8.0, 100 mM NaCl, 0.05% Tween 20, 0.05% NaN₃ and 1% FBS)supplemented with 0.44 nM MAB610 monoclonal Ab (R&D Systems), 0.34 nMruthenylated AF210NA polyclonal Ab (R&D Systems) and 44 μg/mL sheepanti-mouse M280 Dynabeads (Dynal). After a 2 h incubation at roomtemperature with shaking, the reaction is read on the ECL M8 Instrument(IGEN Inc.). A low voltage is applied to the ruthenylated TNF-α immunecomplexes, which in the presence of TPA (the active component inOriglo), results in a cyclical redox reaction generating light at 620nM. The amount of secreted TNF-α in the presence of compound comparedwith that in the presence of DMSO vehicle alone (HI control) iscalculated using the formula: % control (POC)=(cpd−average LO)/(averageHI−average LO)*100. Data (consisting of POC and inhibitor concentrationin μM) is fitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)̂D))),where A is the minimum y (POC) value, B is the maximum y (POC), C is thex (cpd concentration) at the point of inflection and D is the slopefactor) using a Levenburg-Marquardt non-linear regression algorithm. Thedata (IC₅₀ value ranges) for examplary compounds for this assay isprovided in Table 1.

Inhibition of LPS-Induced TNF-α Production in Mice

Male DBA/1LACJ mice are dosed with vehicle or test compounds in avehicle (the vehicle consisting of 0.5% tragacanth in 0.03 N HCl) 30 minprior to lipopolysaccharide (2 mg/Kg, I.V.) injection. Ninety minutesafter LPS injection, blood is collected and the serum is analyzed byELISA for TNF-α levels.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al., Proc. Soc. Exp. Biol.Med., 111:544 (1962); K. F. Swingle, in R. A. Scherrer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology,13(1433, Academic, New York (1974) and collagen induced arthritis (D. E.Trentham et al., J. Exp. Med., 146:857 (1977); J. S. Courtenay, Nature(New Biol.), 283:666 (1980)).

¹²⁵I-Glucagon Binding Screen with CHO/hGLUR Cells

The assay is described in WO 97/16442, which is incorporated herein byreference in its entirety.

Reagents

The reagents can be prepared as follows: (a) prepare fresh 1Mo-Phenanthroline (Aldrich) (198.2 mg/mL ethanol); (b) prepare fresh 0.5MDTT (Sigma); (c) Protease Inhibitor Mix (1000X): 5 mg leupeptin, 10 mgbenzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per mLDMSO and store aliquots at −20° C.; (d) 250 μM human glucagon(Peninsula): solubilize 0.5 mg vial in 575 μl 0.1N acetic acid (1 μLyields 1 μM final concentration in assay for non-specific binding) andstore in aliquots at −20° C.; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1mM DTT and 3 mM o-phenanthroline; (f) Assay Buffer with 0.1% BSA (fordilution of label only; 0.01% final in assay): 10 μL 10% BSA(heat-inactivated) and 990 μL Assay Buffer; (g) ¹²⁵I-Glucagon (NEN,receptor-grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 μL in assaybuffer with BSA (about 50 pM final concentration in assay).

Harvesting of CHO/hGLUR Cells for Assay

1. Remove media from confluent flask then rinse once each with PBS (Ca,Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.).

2. Add 10 mL Enzyme-free Dissoc. Fluid and hold for about 4 min at 37°C.

3. Gently tap cells free, triturate, take aliquot for counting andcentrifuge remainder for 5 min at 1000 rpm.

4. Resuspend pellet in Assay Buffer at 75000 cells per 100 μL.

Membrane preparations of CHO/hGLUR cells can be used in place of wholecells at the same assay volume. Final protein concentration of amembrane preparation is determined on a per batch basis.

Assay

The determination of inhibition of glucagon binding can be carried outby measuring the reduction of I¹²⁵-glucagon binding in the presence ofcompounds of Formula I. The reagents are combined as follows:

Compound/ 250 μM CHO/hGLUR Vehicle Glucagon ¹²⁵I-Glucagon Cells Total—/5 μl — 25 μL 100 μL Binding +Compound 5 μl/— — 25 μL 100 μLNonspecific —/5 μl 1 μl 25 μL 100 μL BindingThe mixture is incubated for 60 min at 22° C. on a shaker at 275 rpm.The mixture is filtered over pre-soaked (0.5% polyethylimine (PEI)) GF/Cfiltermat using an Innotech Harvester or Tomtec Harvester with fourwashes of ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity in thefilters is determined by a gamma-scintillation counter.

Thus, compounds of the invention may also be shown to inhibit thebinding of glucagon to glucagon receptors.

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10% FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 h on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-1b/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng humanIL-1b/mL, and the cells incubated for 18-22 h. Following replacement ofmedia with 190 mL MEM, 10 mL of test compound diluted in HBS is added toachieve the desired concentration and the cells incubated for 4 h. Thesupernatants are removed and replaced with MEM containing 30 mMarachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls. Various compounds of the invention may be shown toinhibit the COX-1 and/or COX-2 activity.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, pro-inflammatorycytokines levels including, without limitation, TNF, IL-1, IL-2, IL-6and/or IL-8, and disease associated therewith. The compounds of theinvention have kinase modulatory activity in general, and p38 kinasemodulatory activity in particular. In one embodiment of the invention,there is provided a method of treating a disorder related to theactivity of p38 enzyme in a subject, the method comprising administeringto the subject an effective dosage amount of a compound of a compound ofFormulas I, II or III.

Accordingly, the compounds of the invention would be useful in therapyas anti-inflammatory agents in treating inflammation, or to minimizedeleterious effects of p38. Based on the ability to modulatepro-inflammatory cytokine production, the compounds of the invention arealso useful in treatment and therapy of cytokine-mediated diseases.Particularly, these compounds can be used for the treatment ofrheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveitis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult respiratory distress syndrome (ARDS),psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection, or any combination thereof, in a subject.

An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful for treatingankylosing spondylitis, inflammatory bowel disease, inflammatory pain,ulcerative colitis, asthma, chronic obstructive pulmonary disease,myelodysplastic syndrome, endotoxic shock, chronic hepatitis C or acombination thereof.

The present invention also provides methods for the treatment of proteintyrosine kinase-associated disorders, comprising the step ofadministering to a subject in need thereof at least one compound of theFormula I, Formula II or of Formula III in an amount effectivetherefore. Other therapeutic agents such as those described below may beemployed with the inventive compounds in the present methods. In themethods of the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

Use of the compound(s) of the present invention in treating proteintyrosine kinase-associated disorders is exemplified by, but is notlimited to, treating a range of disorders such as:

The present invention also provides for a method for treating theaforementioned disorders such as atopic dermatitis by administration ofa therapeutically effective amount of a compound of the presentinvention, which is an inhibitor of protein tyrosine kinase, to apatient, whether or not in need of such treatment.

In yet another embodiment, the compounds are useful for decreasing thelevel of, or lowering plasma concentrations of, one or more of TNF-α,IL-1β, IL-6 and IL-8 in a subject, generally a mammal and typically ahuman.

In yet another embodiment, the compounds are useful for treating a paindisorder in a subject, which is typically a human by administering tothe subject an effective dosage amount of a compound according toFormulas I, II or III.

In yet another embodiment, the compounds are useful for treatingdiabetes in a subject, which is typically a human, by administering tothe subject an effective dosage amount of a compound according toformulas I or II, to produce a glucagon antagonist effect.

In yet another embodiment, the compounds are useful for decreasingprostaglandin production in a subject, which is typically a human, byadministering to the subject an effective dosage amount of a compoundaccording to Formulas I, II or III.

In yet another embodiment, the compounds are useful for decreasingcyclooxygenase enzyme activity in a subject, which is typically a human,by administering to the subject an effective amount of a compoundaccording to formulas I or II.

In yet another embodiment, the cyclooxygenase enzyme is COX-2.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating TNF-α, IL-1, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia with the compounds and/or compositions ofthis invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.01 to 500 mg/kg, advantageously between about 0.01 andabout 50 mg/kg, more advantageously about 0.01 and about 30 mg/kg, evenmore advantageously between about 0.1 and about 10 mg/kg, and even moreadvantageously between about 0.25 and about 5 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable excipient, which includesdiluents, carriers, adjuvants and the like (collectively referred toherein as “carrier” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectivedosage amount of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound; forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day. Formulations suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin (e.g., liniments, lotions, ointments,creams, pastes, suspensions and the like) and drops suitable foradministration to the eye, ear, or nose. A suitable topical dose ofactive ingredient of a compound of the invention is 0.1 mg to 150 mgadministered one to four, preferably one or two times daily. For topicaladministration, the active ingredient may comprise from 0.001% to 10%w/w, e.g., from 1% to 2% by weight of the formulation, although it maycomprise as much as 10% w/w, but preferably not more than 5% w/w, andmore preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base. If desired, the aqueous phase of the cream base may include,for example at least 30% w/w of a polyhydric alcohol such as propyleneglycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethyleneglycol and mixtures thereof. The topical formulation may desirablyinclude a compound, which enhances absorption or penetration of theactive ingredient through the skin or other affected areas. Examples ofsuch dermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other excipients andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I, IIor III with a pharmaceutically acceptable excipient to manufacture themedicament.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of inflammation, the method comprisingcombining an amount of a compound according to Formulas I, II or IIIwith a pharmaceutically acceptable excipient to manufacture themedicament.

COMBINATIONS

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of TNF-α, IL-1, IL-6, and IL-8mediated diseases, cancer, and/or hyperglycemia.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, II and III may also be administered sequentially withknown anti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The compounds of the invention may also be used in co-therapies withanti-neoplastic agents such as other kinase inhibitors, including CDKinhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP),COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib,and etoricoxib, NSAID's, SOD mimics or α_(v)β₃ inhibitors.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein A¹ is CR² or N;A² is CR³ or N; A³ is CR⁴; each of A⁴, A⁵ and A⁶, independently, is CR⁶or N, provided that no more than two of A³, A⁴, A⁵ and A⁶,independently, is N; R¹ is C₁₋₈-alkyl, —OC₁₋₈-alkyl, —SC₁₋₈-alkyl,—NHC₁₋₈-alkyl, —N(C₁₋₈-alkyl)₂, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of which is optionally substituted with 1-5substituents of R⁹, or R¹ is a 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹; eachof R² and R³, independently, is H, halo, haloalkyl, NO₂, CN, C₁₋₆-alkyl,C₁₋₆-alkoxyl, C₁₋₆-thioalkyl, C₁₋₆-aminoalkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl or C₃₋₆-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl and C₃₋₁₀-cycloalkyl optionally substituted with 1-5substituents of R⁹; R⁴ is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹; R⁵ is C(O)NR⁷R⁷,C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁶,independently, is H, halo, haloalkyl, NO₂, CN, OH, C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl, wherein the C₁₋₆-alkyl ofeach is optionally comprising 1-3 heteroatoms selected from N, O and Sand optionally substituted with 1-5 substituents of R⁹; each R⁷,independently, is H, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl andC₃₋-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is a partially or fully saturatedor fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and wherein each ring of said ringsystem is optionally substituted independently with 1-5 substituents ofR⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹,NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or apartially or fully saturated or unsaturated 5-6 membered ring of carbonatoms optionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹; and R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂,acetyl, oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl, provided that R¹ is not —C(Phenyl)₃.2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein each of R⁴ and each R⁶, independently, is H, F, Cl, Br,CF₃, —OCF₃, C₂F₅, —O C₂F₅, —O—C₁₋₄-alkyl, —C₁₋₄-alkyl-O—C₁₋₄-alkyl,—S—C₁₋₄-alkyl, —C₁₋₄-alkyl-S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl,—N(C₁₋₄-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₄-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂,NO₂, NH₂, CN or C₁₋₈-alkyl, the C₁₋₈-alkyl optionally substituted with1-5 substituents of R⁹.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₈-alkyl,—OC₁₋₈-alkyl, —SC₁₋₈-alkyl, —NHC₁₋₈-alkyl, —N(C₁₋₈-alkyl)₂,C₂₋₈-alkenyl, C₂₋₈-alkynyl or C₂₋₈-cycloalkyl, each of which isoptionally substituted with 1-5 substituents of R⁹.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is optionally substituted with1-5 substituents of R⁹.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each of R² and R³,independently, is H.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷,NR⁷C(O)R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸.
 7. Thecompound of claim 6, or a pharmaceutically acceptable salt thereof,wherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is phenyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, thiophenyl, furyl, tetrahydrofuryl,pyrrolyl, tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl,oxadiazolyl, isothiazolyl, morpholinyl, piperidinyl, piperazinyl,pyranyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclorhexyl, each ofwhich is optionally substituted with 1-5 substituents of R⁹; each of R²and R³, independently, is H, halo, haloalkyl or C₁₋₄-alkyl; R⁴ is H, F,Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₆-alkyl, the C₁₋₆-alkyloptionally substituted with one or more substituents of R⁹; R⁵ isC(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁶, independently, is H, F, Cl, Br, CF₃,—OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂,NO₂, NH₂, CN or C₁₋₆-alkyl, the C₁₋₆-alkyl optionally substituted withone or more substituents of R⁹; each R⁷, independently, is H,C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, wherein the C₁₋₁₀-alkyl andC₃₋₁₀-cycloalkyl optionally comprising 1-4 heteroatoms selected from N,O and S and optionally substituted with 1-3 substituents of R⁹; R⁸ is aring selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; andR⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl, provided that R¹ is not —C(Phenyl)₃.9. The compound of claim 1 having a Formula II,

or a pharmaceutically acceptable salt thereof, wherein A¹ is CR² or N;A² is CR³ or N; each of A⁴, A⁵ and A⁶, independently, is CR⁶ or N,provided that no more than one of A³, A⁴, A⁵ and A⁶, independently, isN; R¹ is C₁₋₆-alkyl, —OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, morpholinyl, piperidinyl, piperazinyl, cyclopropyl,cyclobutyl, cyclopentyl or cyclorhexyl, each of C₁₋₆-alkyl,—OC₁₋₆-alkyl, —SC₁₋₆-alkyl, —NHC₁₋₆-alkyl and ring optionallysubstituted with 1-5 substituents of R⁹; each of R² and R³,independently, is H, F, Cl, CF₃, methyl or ethyl; R⁴ is H, F, Cl, Br,CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl, —S-methyl, —NH-methyl,—N(methyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionallysubstituted with one or more substituents of R⁷; R⁵ is C(O)NR⁷R⁷,C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸; each R⁶, independently, is H, F, Cl,Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, OH, —O-methyl, —S-methyl, —NH-methyl,—N(methyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionallysubstituted with one or more substituents of R⁷; each R⁷, independently,is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein the C₁₋₆-alkyl andC₃₋₆-cycloalkyl optionally comprising 1-3 heteroatoms selected from N, Oand S and optionally substituted with 1-3 substituents of R⁹; R⁸ is aring selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland cycloheptyl, wherein said ring is optionally substitutedindependently with 1-3 substituents of R⁹; and R⁹ is H, halo, haloalkyl,CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, —SO₂C₁₋₁₀-alkylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl, provided that R¹ is not —C(Phenyl)₃.10. The compound of claim 9 wherein each of each of A⁴, A⁵ and A⁶,independently, is CR⁶.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, selected from:4-methyl-N-(1-methylethyl)-3-(1-(1-methylethyl)-1H-1,2,3-benzotriazol-5-yl)benzamide;N-cyclopropyl-4-methyl-3-(1-(1-methylethyl)-1H-benzotriazol-5-yl)benzamide;3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide;3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-N-cyclopropyl-4-methylbenzamide;N-cyclopropyl-3-fluoro-5-(1-(4-fluoro-2-methylphenyl)-1H-benzotriazol-5-yl)-4-methylbenzamide;3-(1-(2-chlorophenyl)-1H-benzotriazol-5-yl)-5-fluoro-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide;N-cyclopropyl-3-(1-(1,1-dimethylethyl)-1H-benzotriazol-5-yl)-5-fluoro-4-methylbenzamide;andN-cyclopropyl-3-fluoro-4-methyl-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-benzotriazol-5-yl)benzamide.12. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 13. (canceled) 14.A method of treating Pagets disease, osteoporosis, multiple myeloma,uveitis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,adult respiratory distress syndrome (ARDS), Crohn's disease, allergicrhinitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration,cachexia, Reiter's syndrome, type I diabetes, type II diabetes, boneresorption diseases, graft vs. host reaction, Alzheimer's disease,stroke, myocardial infarction, ischemia reperfusion injury,atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria,sepsis, septic shock, toxic shock syndrome, fever, myalgias due toHIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, theherpes viruses or herpes zoster infection or a combination thereof in asubject, the method comprising administering to the subject an effectivedosage amount of the compound of claim
 1. 15. (canceled)
 16. A method oftreating psoriasis, psoriatic arthritis, rheumatoid arthritis or acombination thereof in a subject, the method comprising administering tothe subject an effective dosage amount of the compound of claim
 1. 17. Amethod of treating ankylosing spondylitis, inflammatory bowel disease,inflammatory pain, ulcerative colitis, asthma, chronic obstructivepulmonary disease, myelodisplastic syndrome, endotoxic shock, chronicHepatitis C or a combination thereof in a subject, the method comprisingadministering to the subject an effective dosage amount of the compoundof claim
 1. 18. A process of making a compound according to claim 1, theprocess comprising the step of reacting a compound 7

wherein A¹, A² and R¹ areas defined in claim 1 and X is a halogen, witha boronic acid having a general formula

wherein A³, A⁴, A⁵ A⁶ and R⁵ as defined in any of claims 1-11, to make acompound according to claim 1.